Somatostatin is a cyclic peptide found endogenously in two major forms made up of 14 (sst-14) or 28 (sst-28) amino acids. The shorter sst-14 is identical in sequence to the C-terminal half of sst-28. Somatostatin is produced widely in the body and acts both systemically and locally to inhibit the secretion of various hormones, growth factors and neurotransmitters. The biological effects of somatostatin are mediated by a family of G protein-coupled receptors, of which five subtypes (SSTR1-5) have been cloned in humans (Reisine and Bell 1995; Patel 1999). The affinities of the two endogenous forms of somatostatin on the five subtypes are relatively similar (sst-28 has been reported to have a moderate preference for the SSTR5). However, the five subtypes are differentially expressed in different tissues and do also show some differences in their interaction with a number of signalling pathways. Thus, the pleiotropic physiological responses mediated by somatostatin are a reflection of its widespread distribution and the existence of multiple receptor subtypes.
Based on their sequence similarity and their affinity towards a number of octapeptide and hexapeptide analogs to somatostatin, the family of five somatostatin receptor subtypes can be divided into two subfamilies: one subfamily made up of SSTR2, SSTR3 and SSTR5 and another subfamily made up of SSTR1 and SSTR4. The former possesses high and the latter rather low affinity towards the aforementioned hexapeptide and octapeptide analogs (Hoyer et al. 1995). Due to the availability of high affinity and selective ligands, the physiology of the SSTR2,3,5 subfamily has been more thoroughly characterized and it appears that the ‘classical’ effects of somatostatin, such as very potent inhibition of growth hormone, insulin, glucagon and gastric acid release, are mediated either primarily or exclusively via members of this subfamily.
Even though the physiology and pathophysiology of the subtypes SSTR1 and SSTR4 are less well understood, there have been a number of findings about the role of these subtypes described in scientific publications and the patenting literature. U.S. Pat. No. 6,124,256 reported that, given their localisation in the vascular wall and their time-related induction during the proliferative stage, SSTR1 and/or SSTR4 may be the optimal subtypes to prevent fibroproliferative vasculopathy via a somatostatin receptor based therapy. In agreement with this, Curtis et al. (2000) have described SSTR1 and SSTR4 to represent the predominant subtypes expressed in human blood vessels and have proposed the use of SSTR1- or SSTR4-selective agonists for the treatment of endothelial cell-mediated proliferative diseases. Aavik et al. (2002) have demonstrated that a purportedly SSTR1- and SSTR4-selective peptide analogue of somatostatin (CH-275) is able to prevent intimal hyperplasia after rat carotid denudation injury. Taken together, these findings may explain why two peptide analogues of somatostatin, octreotide and lanreotide, which possess very high preferences for the subtypes SSTR2 and SSTR5 but have rather low affinities for the subtypes SSTR1 or SSTR4, failed to show efficacy in clinical trials aiming at the prevention of restenosis after percutaneous transluminal angioplasty (Eriksen et al. 1995; von Essen et al. 1997).
Due to the fact that SSTR1 activation causes antiproliferative effects, SSTR1-selective agonist may be useful for the treatment of SSTR1 bearing tumors. For example, it has been described that SSTR1 receptors are expressed in prostate cancer (Sinisi et al. 1997; Reubi et al. 1998; Reubi et al. 2001) but not in normal prostate tissue. Independent of its functional properties as an agonists or an antagonist, any SSTR1 selective ligand may be useful for the diagnosis of prostate tumors or tumors in other tissues expressing the SSTR1 subtype.
WO97/03054 and U.S. Pat. No. 6,221,870 describe benzo[g]quinoline-derived (WO097/03054) or ergoline-derived (U.S. Pat. No. 6,221,870) SSTR1-selective antagonist as lowering aggressive behavior in mice and, based on this observation, suggest such compounds to be useful for the treatment of depression, anxiety, affective disorders and attention deficit and hyperactivity disorders.
According to Bito et al. (1994) the SSTR4 subtype is expressed at high levels in the rat hippocampus where somatostatin has been reported to play a significant role in the regulation of membrane conductance. Since the hippocampus is a brain structure closely linked to learning and memory, as well as mental disorders such as depression and schizophrenia, the prominent role of the SSTR4 subtype in the hippocampus suggests that SSTR4 selective agonists or antagonists with the ability to pass the blood-brain-barrier may have therapeutic potential.
Employing in situ hybridisation, Mori et al. (1997) have shown that in the rat eye SSTR4 expression predominates in the posterior iris epithelium and ciliary body. In addition, the authors have observed that somatostatin lowers intraocular pressure (iop) and, based on these observations, they have suggested that SSTR4-selective ligands may be useful as anti-glaucoma agents.
Somatostatin has a very short biological half-life and is therefore unsuitable for therapeutic use. A number of shorter hexa- and octapeptide analogs of somatostatin with improved biological stability have been identified (e.g. patents U.S. Pat. No. 4,485,101, U.S. Pat. No. 5,409,894 or WO97/47317). However, these abbreviated peptide analogs are heavily biased in favour of the SSTR2,3,5 subfamily and do not show any significant interaction with the subtypes SSTR1 or SSTR4. In contrast, WO97/14715 and Rivier et al. (2001) describe a group of SSTR1 preferring undecapeptide agonists. However, besides their often rather short biological half-lifes peptides also possess other problematic properties, which make them unsatisfactory as medicines. For example, peptides have a very limited ability to penetrate membranes. This is one of the reasons, why it is in most cases impossible to apply peptides via an oral route and why peptides generally do not reach the central nervous system.
In recent years, a number of nonpeptide somatostatin agonists have been identified. Besides the already mentioned SSTR1-selective antagonists reported in WO97/03054 and U.S. Pat. No. 6,221,870, WO97/43278 describes a number of thiourea-based compounds that preferentially interact with the somatostatin SSTR4 and the histamin H3 subtype. U.S. Pat. No. 6,329,389 and U.S. Pat. No. 6,352,982 provide SSTR4-selective compounds centred around tetrahydroquinoline or 4,1-benzoxazepine scaffolds. Rohrer et al. (1998) have been able to identify subtype-selective agonists for each of the five somatostatin receptor subtypes by employing a combinatorial chemistry strategy which incorporated the generally accepted hypothesis on the structure-activity-relationship of somatostatin receptor active compounds that the amino acid residues 8 and 9 in sst-14 (which consist of a tryptophan and a lysine) are essential for proper ligand-receptor interaction.
The current invention describes a new class of somatostatin receptor ligands in the form of sulfonamido-peptidomimetics. These compounds are in part related to sulfonamido-peptidomimetics, which have been presented in Brussaard et al. (1989), WO02/24192 and WO03/026575 in the context of another G-protein coupled receptor family, namely neuropeptide FF receptor. Sulfonamide derivatives of monocyclic or bicyclic amino acids have also been described in U.S. Pat. No. 6,271,252 and U.S. Pat. No. 6,221,888 as cell adhesion molecule (CAM) antagonists which inhibit leukocyte adhesion and leukocyte adhesion-mediated pathologies.